The present invention relates to an active substance-containing patch for the controlled release of estradiol or its pharmaceutically acceptable derivatives either alone or combined with gestagens, to human or animal skin, comprising a pressure-sensitive adhesive of ethylcellulose, esters of colophony, and lauric acid. The present invention further relates to its use and to a process for its production.
Estrogen-containing patches have been known for some time. However, these patches are disadvantageous in that they either contain ethanol or involve the potential danger of active substance recrystallization in the course of time.
It is known from DE-OS 32 05 258 and EP 0 285 563 to administer estradiol and ethanol simultaneously in a patch formulation. However, the production of this patch is very expensive, and there is a low wearing comfort after application because of inflexibility.
EP 0 285 563 describes a transdermal therapeutic system for the combined application of estrogens and gestagens. The reservoir comprises the active substance formulation, and optionally a membrane, as well as ethanol as a percutaneous absorption improving agent. Since the active substance release is primarily controlled by the membrane, this transdermal therapeutic system is completely different from the active substance-containing patch according to the present invention. In the patch described in said publication, the adhesive has the mere function of fastening the patch to the skin. The fact that it can contribute to the control of the active substance release is not its main function but merely a--probably even undesired--side effect. It is a so-called "pouch patch" since the active substance preparation is present in a pouch consisting of an impermeable backing layer and a membrane having an adhesive layer. Owing to its complicated structure production of this patch is very expensive since the individual components have to be manufactured separately and then joined in an additional step to form a patch.
Unlike the single-layer system according to the present invention EP 0 275 716 describes a two-layer transdermal system for the simultaneous administration of one or several estrogens which are dissolved or microdispersed in the polymeric layer. In addition to the active substances, the pressure-sensitive adhesive layer comprises substances improving the transdermal absorption. Polymeric and pressure-sensitive adhesive layer may consist of polyacrylates, silicones, or polyisobutylenes.
EP 0 072 251 describes a flexible, liquid-absorbing medicinal bandage. The substrate attached to the flexible backing layer consists of a hydrophilic matrix based on hydrophilic high-molecular polysaccharides and/or polyacrylic acid, polyacrylamide, ethylene-vinyl acetate-copolymers, and other polymers, as well as of a liquid phase based on a solution or emulsion of carbohydrate, proteins, polyhydric alcohols, and different active substances, amongst others hormones. The main feature of this invention is the moisture-absorbing adhesive.
EP 0 328 806 describes a transdermal therapeutic system without membrane; its matrix consists of a polyacrylate adhesive, a solvent, a penetration enhancer, and estrogen, its derivatives and combinations thereof.
WO 87/07 138 describes an estradiol patch having a backing layer, an active substance-containing matrix, and a pressure-sensitive adhesive covered with a removable protective layer. Matrix and pressure-sensitive adhesive are manufactured in operations involving considerable technological expenditure, i.e., by homogenizing, degassing, coating, drying, and separating. According to an embodiment the backing layer has to be coated with a pressure-sensitive adhesive, requiring an additional operation. The individual parts are joined in a separate step. For this reason, the production of this patch is very expensive and complicated.
U.S. Pat. No. 4,624,665 describes systems comprising the active substance in microencapsulated form within the reservoir. The reservoir is embedded between backing layer and a membrane. The outer edge of the system is provided with a pressure-sensitive adhesive. Structure and production of this system are very complicated since the active substance has to be microencapsulated and homogeneously dispersed in a liquid phase which is then embedded between backing layer and membrane in further operations. Moreover, this system must then be provided with an adhesive edge and covered with a protective layer.
EP 0 186 019 describes active substance patches wherein water-swellable polymers are added to a rubber/adhesive-resin-mass and from which estradiol can be released. It turned out, however, that the estradiol release from these active substance patches is absolutely insufficient and fails to meet the therapeutic requirements.
DE-OS 20 06 969 describes a patch or a pressure-sensitive adhesive dressing exhibiting system action, wherein contraceptive substances are incorporated in the adhesive component or in the adhesive film. The adhesive film may be an acrylate.
DE-OS 39 33 460 describes an estrogen-containing active substance patch based on homo and/or copolymers with at least one derivative of acrylic acid or with methacrylic acid combined with water-swellable substances.
However, it turned out that the active substance release of pressure-sensitive adhesive transdermal therapeutic matrix systems which comprise the active substance in a partially or completely dissolved form is absolutely insufficient; moreover, they involve the potential risk that the active substance recrystallizes in the course of time. As a result the active substance release decreases, and the estrogen-containing patch does no longer meet the therapeutic requirements.